Since nuclei in muscle fibers of vertebrate animals are incapable of DNA synthesis or mitotic division, increases in muscle fiber numbers or in numbers of muscle fiber nuclei are due to proliferation and subsequent differentiation of skeletal muscle precursor cells known as "myoblasts." In adults, myoblasts remain as a mitotically quiescent reserve precursor population which can, upon muscle injury, re-enter the cell cycle, undergo several rounds of proliferation, and subsequently differentiate and permanently exit the from the cell cycle. Upon differentiation, differentiated myoblasts ("myocytes") acquire the ability to fuse with one another or with muscle fibers, and also commence coordinate expression of a large set of muscle-specific myofibrillar and contractile proteins (e.g., muscle myosins and actin, troponin, tropomyosin, etc.).
Muscle tissue can grow by several different mechanisms which are controlled by different trophic factors. Muscle tissue can grow by hypertrophy, an enlargement of or increase in mass or size of muscle fibers, or by hyperplasia, an increase in the numbers of fibers or in the numbers of muscle nuclei, or by a combination of these two processes. Growth factors that act on skeletal muscle tissue can be divided into two broad groups. The factors that stimulate proliferation of myoblasts usually inhibit differentiation of myoblasts and inhibit the expression and action of the muscle regulatory transcription factors (MRFs). Conversely, the factors that stimulate differentiation of myoblasts usually stimulate expression of the MRFs and can contribute to muscle hypertrophy. Most pharmacologic agents currently under consideration as muscle trophic factors act to stimulate muscle hypertrophy. Such hypertrophic factors include, for example, growth hormone (GH) or insulin-like growth factor-I (IGF-I). Muscle hypertrophy can be assessed by the measurement of muscle fiber diameter in vivo or in vitro, or by the measurement of the accretion of the muscle-specific myofibrillar and contractile proteins.
Clinically, a decline in such skeletal muscle tissue mass, or muscle atrophy, is an important contributor to frailty in older individuals. In human males, muscle mass declines by one-third between the ages of 50 and 80. In older adults, extended hospitalization can result in further disuse atrophy leading to a potential loss of the ability for independent living and to a cascade of physical decline. Moreover, the physical aging process profoundly affects body composition, including significant reductions in lean body mass and increases in central adiposity. The changes in overall adiposity and fat distribution appear to be important factors in many common "age-related" disorders such as hypertension, glucose intolerance and diabetes, dyslipidemia, and atherosclerotic cardiovascular disease. In addition, it is possible that the age-associated decrement in muscle mass, and subsequently in strength and endurance, may be a critical determinant for functional loss, dependence and disability. Muscle weakness is also a major factor prediposing the elderly to falls and the resulting morbidity and mortality. Complications from falls constitute the sixth leading cause of death among people over 65 years of age.
Treatment of musculoskeletal frailty with trophic factors such as growth hormone or IGF-I can be associated with significant deleterious side effects including salt retention, edema, elevations in blood pressure, insulin resistance, hyperglycemia, hypoglycemia, gynecomastia, carpal tunnel syndrome and disuse myalgias/arthralgias. Such side effects are likely due to the pleiotrophic effects of these factors on many tissues and metabolic processes. Similarly, treatment with estrogens or androgens, which in some studies have been shown to increase muscularity or bone density, may coincidentally increase the risk of neoplasms. Thus, there exists a need for a muscle-trophic factor that has more specific actions to stimulate muscle hypertrophy, and ultimately, muscle mass. Measures that reduce or reverse the loss of skeletal muscle mass will lead to increased capacity for independence for elderly individuals and thus increased quality of life, as well as a reduction in health care expenditures. A factor that does not stimulate myoblast proliferation would be of particular value.